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Temperature-controlled transport
operations
Technical supplement to
WHO Technical Report Series, No. 961, 2011
Annex 9: Model guidance for the storage and transport of time and
temperaturesensitive pharmaceutical products
January 2014
World Health Organization 2014
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expressed in this publication.
Acknowledgments
The author of this document is Kevin ODonnell, Exelsius Cold Chain Management
Consultancy and member of the United States Pharmacopeia Expert Committee of
Packaging, Storage and Distribution 2010-2015 cycle. Contributions to the document have
also been made by Jim Bacon, Senior Director, Demand Planning and International
Customer Operations - US Office, Grifols, Inc.
Contents
Acknowledgments ................................................................................................................................ 1
Contents ................................................................................................................................................... 2
Abbreviations ........................................................................................................................................ 3
Glossary ................................................................................................................................................... 4
1.
Introduction .................................................................................................................................. 8
1.1 Requirements ...................................................................................................................................... 8
1.2 Objectives.............................................................................................................................................. 8
1.3 Target readership .............................................................................................................................. 8
2.
Guidance .......................................................................................................................................10
2.1 Associated materials and equipment ...................................................................................... 10
2.2 Available shipping systems ......................................................................................................... 10
2.2.1
2.2.2
2.2.3
2.2.4
2.2.5
2.3.2
2.7.2
Abbreviations
AWB
CI
Chemical Indicator
CRT
ETI
EDLM
IATA
NOTOC
Notice to Captain
PDA
SLA
SOP
TTI
Time-Temperature Integrator
TTSPP
ULD
URS
Glossary
3PL: Third party logistics provider: a firm that provides service to its customers of
outsourced (or "third party") logistics services for part, or all of their supply chain
management functions.
4PL: Fourth party logistics provider: a general contractor who manages other 3PLs,
truckers, forwarders, custom house agents, and others, essentially taking responsibility for
a complete logistics process for the customer.
Active systems: Externally powered or on-board powered systems using electricity or
other fuel source to maintain a temperature-controlled environment inside an insulated
enclosure under thermostatic regulation (e.g. cold rooms, refrigerators, temperaturecontrolled trucks, refrigerated ocean and air containers).
Advanced Phase Change Materials (PCMs): Temperature stabilizing media (sometimes
referred to as refrigerants), chemically engineered so that their latent heat of fusion
occurs at a temperature other than zero C, phasing from one state of matter to another
(i.e. liquid to solid) at a pre-formulated temperature. Such materials are typically
comprised of oils, salts, or paraffin.
Ancillary packaging components: Packaging elements used to protect the TTSPP and
support or enhance performance of the completed package. This may include retainers,
dunnage, secondary protective packaging, and temperature data logging devices.
Chemical indicators: (also called markers or phase-change indicators), are generally
impregnated onto a paperboard substrate. These indicators, sometimes referred to as
critical temperature indicators, are based on a phase change or chemical reaction that
occurs as a function of temperature. Examples include liquid crystals, waxes, polymers,
and lacquers that change phase, and thereby their appearance, as a function of
temperature. Chemical temperature threshold indicators may be reversible or irreversible
and are suitable for high or low temperatures. Temperature threshold indicators show a
response and typically are single-use devices. These indicators provide a signal only when
exposed to temperatures higher than (ascending indicator) or lower than (descending
indicator) a predetermined threshold temperature.
They typically use liquid diffusion technology to signal when a single event timetemperature threshold has been exceeded by irreversibly changing colour, either
instantaneously or with some time delay. The active colloidal substance in freeze
indicators is typically composed of particles of material evenly distributed within a liquid.
At a specific relative temperature the particles in the marker colloid become unstable,
eliminating the repulsive forces that keep the particles separate. The chemicals coagulate,
resulting in a change of colour. The accuracy and precision of these indicators depend to
some extent on human interpretation.
Electronic temperature monitoring and event logger system: A system for recording
and reporting air and/or product temperatures, with optional facilities for recording and
reporting specific events such as door-opening or defrost cycles and for issuing alarms.
Such systems may be user-programmable may also be remotely monitored via a satellite
link.
3 PDA Technical Report No. 39: Guidance for Temperature Controlled Medicinal Products:
Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation
Environment, 2007.
1.
Introduction
This technical supplement has been written to amplify the recommendations given in
WHO Technical Report Series No. 961, 2011, Annex 9: Model guidance for the storage and
transport of time- and temperature-sensitive pharmaceutical products4, section 6.4 and 6.5.
It provides guidance on how to condition, load and handle equipment used to transport
TTSPPs in order to maintain these products with a pre-defined operating temperature
range. The supplement covers refrigerated and temperature-controlled transport vehicles
and active and passive shipping containers. Fixed storage systems, such as cold rooms and
refrigerators, are outside the scope of this document.
The following Technical Supplements are also relevant:
1.1
Requirements
Packaging systems should be validated before use. Generally speaking, the shipper is
responsible for ensuring product temperature compliance during transport.
1.2
Objectives
Provide a general technical introduction to the active and passive packaging and
transport systems used for distributing TTSPPs.
Describe the correct use of the various types of temperature and humidity
monitoring device.
1.3
Target readership
This technical supplement is intended for all those responsible for the transport of TTSPPs
through the supply chain from one fixed storage point to another.
Staff responsible for transport operations need to understand the importance of
pharmaceutical product temperature stability, have a sound working knowledge of
applicable logistics and transport methodologies within their organizations, and they
should understand the basic concepts of packaging thermodynamics and good
documentation practice. They should have a good knowledge of the various types of
4
http://apps.who.int/medicinedocs/documents/s18683en/s18683en.pdf
temperature monitoring device used in the transport environment, together with their
strengths, weaknesses and appropriate uses. They must also be able to train and supervise
junior staff so that they are able to carry out the tasks described below in a reliable and
consistent manner.
2.
Guidance
This section describes the processes that need to be followed to ensure safe transport of
TTSPPs by road and air. The options available for ocean transport are briefly covered. For
general guidance on importation and port clearance procedures readers should also refer
to Chapter 24 of MDS-3: Managing Access to Medicines and other Health Technologies
Importation and port clearing and to the IATA document: Temperature Control
Regulations: The Global Standard for the Safe Transportation of Healthcare Products by Air.
2.1
2.2
Temperature control during ground air or ocean transport can be maintained using either
active or passive shipping systems, as described below.
2.2.1
Refrigerated vehicles
This category includes vans, rigid trucks and semi-trailers have an insulated
thermostatically controlled cargo compartment which is maintained within the labelled
temperature range of the products being transported by means of a dedicated
refrigeration unit. Vans and small rigid trucks typically have refrigeration units powered
directly by the vehicles engine. Larger rigid vehicles and semi-trailers have independent
diesel-powered refrigeration units. Both types may also have electrical back-up so that
they can be mains-powered whilst parked. All refrigerated vehicles should be equipped
with an on-board electronic temperature monitoring and event logger system.
Refrigerated vehicles must be properly qualified to operate on designated routes. They
should only be used in operating environments that are able to manage the equipment,
and over roads which will not damage the vehicles. Refer to Technical Supplement:
Qualification of temperature-controlled road vehicles.
2.2.2
Temperature-controlled vehicles
These are similar to refrigerated vehicles, except that the vehicle itself simply moderates
the ambient temperature, either by heating or cooling. The transported product is
generally packed in a qualified passive shipping system designed to keep it within the
labelled temperature range. The temperature-controlled environment in the vehicle
serves to extend the autonomy of the passive shipping system and protect the product
from temperature extremes. Care must be taken not to subject the packages to
refrigerated temperatures (e.g. +2C to +8C) for extended periods because this risks
freezing the package contents. Ideally, every effort should also be made to avoid exposure
of active and passive packaging to temperatures below +15C. In order to ensure this,
10
Reusable container
11
The typical active shipping system is a dedicated portable container. They come in two
types: systems with cooling only, and systems with both heating and cooling. The
temperature stabilizing medium in active shipping systems typically comprise dry ice
(cooling types only) or use phase change materials (heating and cooling types) as a means
to provide temperature control, although compressor-driven cooling systems are also
used. These containers are either powered by on-board batteries, or use an external
electrical source to run on-board compressors or heat pumps. Thermostatic control is
used to activate the cooling or heating mechanism and circulating fans help to maintain
temperature within specified limits around the enclosed product. Larger containers are
generally leased from the manufacturer, or by an air or ocean carrier, or by a third party
logistics service provider. Figure 2 shows an example.
Figure 2 Active air transport container type LD3
2.2.5
High performance ocean containers, specifically designed for transport of TTSPPs have
recently been developed6. These use a refrigeration and air circulation system running off
the ships on-board power supply, and incorporate integrated satellite tracking. Current
availability of these containers is very limited. Similarly, the availability of oldergeneration refrigerated containers is often scarce, transport times are lengthy, the risk of
mechanical failure is high, and close logistics monitoring is necessary for transport to and
from ports. The refrigeration systems of all ocean containers require an external power
source either electricity or an integrated gas powered generator. As with air cargo, the
See: http://www.blueyellc.com/download/Blueye_Sea_Container.pdf
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greatest risk is temperature exposure in port before loading and unloading. Unfortunately,
this time is often measured in days, not hours. Historically, the pharmaceutical industry
has shied away from the ocean transport option because of concerns over long transport
times, environmental exposure at sea such as temperature and humidity, loss at sea, and
port security concerns. In addition, most shipping lines refuse such shipments because of
the high liability involved. For all these reason, the operational management of these
systems is not discussed further.
2.3
The shipper is responsible for ensuring that the packaging and the mode(s) of transport
used to distribute TTSPPs are capable of maintaining the products within their specified
temperature and humidity ranges. Accordingly, the detailed requirements for each type of
transport operation must be fully defined and suitable transport service providers
identified and appointed. The correct way to do this is to draw up a User Requirements
Specification (URS). This document should clearly define the following:
The temperature and humidity parameters that must be maintained for each
product or product type; these parameters are determined by the product label, or
when acceptable, the manufacturers stability data;
The URS can be used as a basis for developing SOPs and work instructions for in-house
transport operations, and/or a Service Level Agreement for contracted-out transport
services.
2.3.2
Shippers and other transport service provider stakeholders should operate under the
terms of an SLA, which specifies the target and minimum levels of performance, service,
operation or other attributes as set out in the URS. In-house transport services should be
controlled with a similar level of rigour. An SLA should contain the following elements:
Introduction:
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Commencement date;
Scope of work:
Standard service(s);
Non-standard service(s);
Changes to service.
Compensation:
Fee tariff;
Invoicing arrangements;
Payment terms.
Service benchmarks;
Problem management:
Support services;
Problem identification;
Approvals.
Liability;
2.4
14
15
Type of control
Airport tarmac/apron
Aircraft hold
Temperature/humidity monitoring
The following sub-sections set out the content of the checklists needed to operate three
distinct types of shipping system:
Each of the checklists follows the same sequence: pre-shipment actions; actions on the day
of shipment at the point of origin; actions during transit; actions on the arrival day at the
destination and, finally, post-shipment actions.
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2.5
g. Ensure that the designated vehicle is in good working order, that its service record
is up-to-date and that the driver has carried out the relevant daily safety
inspection.
Shipping day: actions at point of origin:
a. Confirm booking, pick-up time and location.
b. Pack the product in its correct tertiary package and attach temperature monitoring
devices to suit the routing requirements. Keep product under proper storage
conditions until the time of despatch.
c. Before loading, pre-condition the product and the refrigerated vehicles cargo area
of the to the same transport temperature.
d. Ensure that the thermostatic controller on the transport vehicle is set to the
required temperature and ensure that the temperature recording device(s) are
operating properly.
For details of suitable systems refer to Technical Supplement: Temperature and humidity
monitoring systems for transport operations.
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a. Check that vehicles refrigeration unit is operating properly and that the
temperature has stabilized. Keep loading door(s) closed until it is time to load the
product. Drivers must ensure the correct temperature setting has been selected.
e. Load product without delay. Do not overload the vehicle. Allow for air circulation
around all sides of the product. Properly block and brace the load, as shown in
Annex 1, to avoid shifting during transit. Close door(s) and apply security seal
and/or lock if required.
f.
If the refrigeration unit has been operating on mains electric power during loading,
make sure that engine-powered refrigeration system is operating correctly and
that the temperature has stabilized within pre-defined limits before releasing.
g. Provide clear instructions to the driver covering the correct load temperature,
handling and transport requirements.
h. Provide emergency contact information to the driver.
i.
Ensure that all paperwork and checklists are completed by responsible parties.
Ensure all checklists and arrival forms are completed by the responsible parties.
2.6
Covered vehicles should be used for transporting passive containers so that shipments are
not exposed to the sun or to the elements. The action sequence below should be followed.
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Pre-shipment actions:
a. Ensure that there are sufficient quantities of all packaging components to
accommodate the shipment on the shipping day.
b. Ensure that all components have been conditioned to the correct temperature (i.e.
temperature stabilizing media, whether frozen or refrigerated).
c. Ensure that the designated vehicle is in good working order, that its service record
is up-to-date and that the driver has carried out the relevant daily safety
inspection.
Shipping day: actions at point of origin:
a. Prepare and pack product in its designated secondary or ancillary packaging. If
possible, keep product under correct storage conditions until it is placed in the
container.
b. Assemble the passive shipping system in accordance with the manufacturers
instructions.
c. Load the product without delay. Do not overload containers.
d. Add temperature data loggers or temperature indicators if required. Place in close
proximity to the product. Do not allow them to come in contact with temperature
stabilizing media.
e. Add dunnage if necessary to prevent the product from shifting during transit.
f.
Ensure that all paperwork and checklists are completed by the responsible parties.
2.7
19
Cargo Regulations Chapter 17 is the industrys framework for meeting Good Distribution
Practices (GDP)8. The purpose of the regulations is to:
Many air carriers offer branded services with defined procedures based on GDP to meet
the specific needs of TTSPPs. Any variation or deviation from such a branded service
should be defined and negotiated beforehand in a specific SOP.
In order to minimize risk, shippers should always collaborate with the air carrier, either
directly or through the designated freight forwarding agent. It is essential to do this in
order to define and agree the service level needed to meet the shippers requirements.
Temperature control within the cargo holds of most aircraft is limited and wide variations
can occur throughout the hold; these variations depend upon placement, location, time at
altitude, and the duration of the flight. However, the greatest and most frequent
vulnerability to temperature exposure occurs on the airport tarmac when goods are
exposed to the elements before aircraft loading, or during unloading. Every precaution
should be made to limit this exposure. Shippers are encouraged to work with their air
service suppliers to minimize tarmac times.
2.7.1
Four different business models are used for the transport of TTSPPs by air: legacy carriers;
integrators; cargo only carriers, and charters. Within each category, carriers will have
different service offerings and service levels tailored to the handling requirements of
specific cargo.
Commercial airlines: These companies operate both passenger and cargo services
and have the advantage that they service a wide range of destinations. Most of
these carriers subcontract services for aircraft handling, ground handling and
warehousing operations. A commercial airlines cargo business usually comes from
freight forwarders and the airline involvement is limited to airport-to-airport
activities. Some may offer road feeder services at origin or destination. Otherwise,
a freight forwarding agent coordinates that effort.
Integrators: These operate large scale door-to-door mail and express delivery
services. Their product offerings are integrated under a single brand identity (i.e.
FedEx, DHL and UPS). They generally deal directly with the shipper rather than a
freight forwarder.
Cargo only carriers: These companies do not carry passengers; they operate
dedicated freighter aircraft and can carry large cargo payloads. Network s are not
8 GDP requirements embrace the activities of phamaceutical manufacturers, shippers, 3PLs, 4PLs,
cargo agents, freight forwarders, independent air carriers, airlines, packagers and active solution
platform providers, warehousing agents and ground handlers.
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as extensive as the commercial airlines, which operate on a hub and spoke model.
Cargo only carriers often sign contracts with large, international freight
forwarders to ensure cargo space availability. Their services may include ground
pick-up and delivery. As with commercial airlines, their ground handling
operations are often subcontracted.
2.7.2
Since July 2012, the IATA Time and Temperature Sensitive label, shown in Figure 3, has
been mandatory for the transport of healthcare cargo shipments. There are however,
specific conditions for proper use of the label. These can be found in the current edition of
the IATA Perishable Cargo Regulations, Chapter 17: Logistics for Temperature Sensitive
Healthcare Products.
Figure 3 Example of IATA Time and Temperature Sensitive label
The principal rules for the correct use of the label are as follows:
Shipments must be booked under the proper handling code and as temperaturecontrolled healthcare cargo in accordance with the IATA Perishable Cargo
Regulations
The label may be applied to both active and passive shipping systems.
The lower half of the label must indicate the external handling temperature range
or limit (minimum and maximum) that the package can be exposed to during
transport.
The temperature range on the label must match the temperature range or limit
stated on the AWB, SLA and/or SOP.
The text must be in English and temperatures must be shown in degrees Celsius.
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Only one label is required. This must be visible on the outermost means of
containment (box, over-pack, or ULD).
2.8
Air transport operations must be tightly managed. In addition to the tasks that must be
carried out to ensure the safe arrival of a specific shipment see Section 2.9 there are a
number of higher level precursor and recurrent actions that need to be taken. These are
described below.
The shipper should:
2.9
The actions described below apply to both active and passive shipping systems, unless
specifically identified.
Pre-shipment actions:
a. Obtain confirmation from the consignee to ship the product (e.g. purchase order or
requisition).
b. Verify product dimensions and determine the type of container required.
c. Notify the freight forwarder of the shipping date and book the shipment. The
freight forwarder must coordinate the transport chain and booking with the air
carrier;
d. Communicate instructions to the freight forwarder regarding pick-up, transport
and handling requirements, including transport temperature requirements.
e. Prepare shipping documentation, including checklists and air waybill (AWB) and
review with the freight forwarder.
f.
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g. Before releasing the container to the airline, ensure that it is operating correctly
and that the temperature has stabilised.
h. Transport to the airline and hand off. From this point onward the airline is
responsible for maintaining the appropriate ambient temperature during storage
and flight, for checking power and for re-icing the container if required, in
accordance with the relevant SOP.
i.
j.
Ensure all checklists are completed by responsible parties in accordance with the
SOP.
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j.
Transport the product from the departure airport to the destination airport.
k. Store the product at transit airports in an area kept within the specified handling
temperature range.
l.
Freight forwarder assists with customs clearance and logs receipt of the product
from the service provider.
g. Provide clear instructions for either unloading the container at the airport or for
transporting to the consignee.
h. Inspect goods for physical damage and evidence of temperature abuse.
i.
j.
Consignee receives product, retrieves and deactivates EDLMs for data retrieval, if
applicable.
24
A similar international shipping procedure has been developed by UNICEF Supply Division
specifically for shipping vaccines in passive containers. This process, together with the
UNICEF Vaccine Arrival Report form, is described in EVM-SOP-E1-02: Vaccine arrival
procedures.
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References
IATA. Temperature Control Regulations: The Global Standard for the Safe
Transportation of Healthcare Products by Air.
https://www.iata.org/publications/Pages/temperature-control-regulations.aspx
Management Sciences for Health. MDS-3: Managing Access to Medicines and other
Health Technologies. 3rd Edition. Kumarian Press, 2011. Available free on-line at:
http://www.msh.org/resources/mds-3-managing-access-to-medicines-andhealth-technologies
ODonnell, K., Wright, A. Good Distribution Practices by Air, Road & Ocean
Workbook and Resource Guide, Excelsius Cold Chain Management, 2013.
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Revision history
Date
Change summary
Approved
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